(S)-1,1-Diphenylprolinol the principal compound of structure 3 is a known compound and has been prepared by a variety of processes, all involving a fully protected pyrrolidine. See for example Enders et al., Org. Synth., Col. Vol. 5, 542-549; Corey et al., J. Amer. Chem. Soc., 1987, 109, 7926-7927; French Patent FR 3638M, 1965; Kapfhammer, et al. Hoppe-Seylers Zeit. Physiol. Chem. 1933, 223, 43-52; German Patent DE 3609152A1, 1987; Corey et al., J. Amer. Chem. Soc., 1987, 109 5551-5553; J. Org. Chem. 1988, 53, 2861-2863; Enders et al., Bull Soc. Chem. Belg., 1988, 97, 691-704. These prior art processes involve multiple steps and rather low overall yields.
For example preparation of (S)-1,1-diphenylprolinol via the procedure described in the literature [Corey et. al., J. Am. Chem. Soc. 1987, 109, 5551-5553] afforded a 30-40% overall yield of the amino-alcohol from (S)-proline. The process required multiple isolations [N-(benzyloxycarbonyl)-(S)-proline (solid, commerically available), N-(benzyloxycarbonyl)-(S)-proline methyl ester (viscous oil), and (S)-1,1-diphenylprolinol hydrochloride (solid, precipitated from diethyl ether), and (S)-1,1-diphenylprolinol (solid recrystallized from water/methanol)]. The Grignard addition to N-benzyloxycarbonyl)-(S)-proline methyl ester required a large excess (8 equiv) of phenylmagnesium chloride. The inital addition to form the intermediate 1,1-diphenylprolinol oxazolidinone occurs quickly at 0.degree. C. The addition of phenylmagnesium chloride to the oxazolidinone affording the desired product, however, is much slower--requiring 12-18 hours at room temperature. Isolation of the amino-alcohol from the large excess of magnesium salts also was a problem--requiring multiple extractions from a magnesium hydroxide gel. The resultant product had an enantiomeric purity of 99:1 (S:R) by capillary GC (DB-23) of the Mosher amide derivative. ##STR8##
The methods reported for preparation of structure 1 (n.dbd.1, Ar.dbd.Ph, R.dbd.Me, R.sup.1, R.sup.2 .dbd.H), include reaction of the corresponding prolinol with methylboronic acid (1.1 equiv:1) in toluene at 23.degree. C. in the presence of 4 .ANG. molecular sieves for 1.5 hours; or 2) in toluene at reflux for 3 hours using a Dean-Stark trap for water removal; both followed by evaporation of solvent, and molecular distillation (0.1 mm, 170.degree. C.) (Corey et al., J. Amer. Chem Soc., 1987 109, 7925-7926). An Alternate method reported for preparation of structure 1 (n.dbd.1, Ar.dbd.2-naphthyl, R.dbd.Me, R.sup.1 R.sup.2 .dbd.H) involved heating a toluene solution of the corresponding prolinol and methylboronic acid (1.2 equiv) at reflux for 10 hours using a Soxhlet extractor containing 4 .ANG. molecular sieves (Corey et al., Tetrahedron Lett., 1989, 30, 6275-6278). The key to these procedures is irreversible removal of two molecules of water, thus driving the reaction to completion. Chiral reductions using oxazaborolidine prepared via these methods provided erratic results with respect to yields and enantiomeric purity of the reduction products.
Now, with the present invention there is provided a novel improved procedure for preparation of the diarylmethanol 3; a novel improved method for the preparation of the oxazaborolidine catalyst, 1; and novel improved catalysts.